In the absence of noise or other ototoxins, age-related hearing loss is largely the result of the degeneration of specific non-sensory cells in the cochlea resulting in metabolic presbyacusis. Unlike sensory hair cells that are unable to regenerate, non-sensory cells, such as fibrocytes in the spiral ligament and glia-like cells in the auditory nerve, are able to repopulate themselves after injury, although their regenerative ability seems to decline with age. The mechanism whereby these non-sensory cells are able to repair themselves remains unknown. Recent investigations have shown that bone marrow (BM) stem cells have the potential to differentiate into multiple non-hematopoietic cell lineages with the caveat that aged BM stem cells are less effective at homing, engraftment and differentiation. Our studies have documented that some non-sensory cochlear cells in the adult mouse are continually derived from hematopoietic stem cells (HSCs). Moreover, we have shown that engraftment of the HSC-derived cells in the cochlear lateral wall and auditory nerve is significantly increased after fibrocytes and spiral ganglion neurons are chemically injured. Here, we propose to determine whether human inner ear cells are derived from HSCs using human-murine xenograft models (humanized mice). Our central hypotheses are that certain cell types in the human inner ear are continually derived from HSCs, and that HSC aging and cochlear injury significantly affect stem cell engraftment and differentiation. Three specific aims are proposed. Aim 3.1 determines the potential of human stem cells isolated from cord blood to engraft and differentiate into specific cochlear cell types. Aim 3.2 determines the extent to which BM stem cells from younger and older human subjects, especially those with metabolic presbyacusis, differ in their abilities to engraft and differentiate in the inner ear. Aim 3.3 tests the effects of cochlear injury on the engraftment and differentiation of BM stem cells from younger and older human subjects. The aged stem cells will be isolated from the BM of older human subjects with normal hearing and with metabolic presbyacusis as determined by auditory performance measures in the Human Subjects Core. This translational project will help further the understanding of how BM cells contribute to cellular homeostasis in the human inner ear. Such knowledge will provide the intellectual foundation needed to design treatments for age-related hearing loss, especially metabolic presbyacusis.